From the Richard & Rhoda Goldman School of Public
Policy
& Center for the Economics and Demography of Aging, University of California, Berkeley
(Dr. Banks); and Michigan State University College of Human Medicine, East Lansing (Dr.
Fossel).

Population projections of the aging global society and its
fiscal and social impact have depended on assumptions regarding the human life span. Until now,
the assumption that the maximum human life span is fixed has been justified. Recent advances in
cell biology, genetics, and our understanding of the cellular processes that underlie aging,
however, have shown that this assumption is invalid in a number of animal models and suggest
that this assumption may become invalid for humans as well. In vitro alteration of telomeres
affects cellular senescence, and in vivo manipulation of genes and diet can increase maximum
life
span in animal models. If these discoveries are extended to humans, we may soon be able to
extend the maximum human life span and postpone or prevent the onset of diseases associated
with aging. Such a possibility requires that we recognize a growing uncertainty in any attempt to
project international health care costs into the next few decades. The costs may be significantly
lower than projections, if life span increases and age-related disabilities are postponed or less
severe, or perhaps higher, if life span increases without altering the onset and severity of
disability.
An appropriate uncertainty regarding the human life span undermines any attempt to accurately
predict health costs in the next century.

The same forces which operate in the birth and temporal
existence of the human being operate also in his destruction and death.

Maimonides

The Guide for the Perplexed

HISTORICALLY, there has been an-- as yet
well-founded-assumption that although we may alter the course of age related diseases, such as
emphysema by smoking cessation and atherosclerosis by lowering cholesterol and blood
pressure,
the underlying process of aging cannot itself be altered [1]. The actual life span of any single
individual is determined by a multitude of factors including lifestyle, socioeconomic status, diet,
environmental conditions, and genetic endowments [2,3]. Some of these factors can be altered
with consequent alteration of the individual (or the mean) life span, but not with any known
increase in the maximum human life span. Currently, the longest anyone has ever lived is 122
years [4]. The biological origin of this maximum life span has been controversial. Is there a
"clock" regulating the aging process? Or is there a biological limit that cannot be surpassed--
irrespective of our genes? These are questions that gerontologists, geneticists, and molecular and
cell biologists have been pondering for decades.

Recently, there has been a conceptual shift in our understanding of
aging. The possibility of extending the maximum human life span has gone from legend to
laboratory [5]. This change has been prompted by a growing academic literature that suggests,
that the aging process itself, as well as the consequent and fundamental cellular changes that
occur in age-related diseases, is modifiable. This revision in views, if borne out, has profound
clinical implications for the incidence of age-related diseases. Furthermore, the fiscal impact on
government expenditures in the areas of health and social security will be perplexing even if only
a
modicum of these views hold true.

Aging is often seen from two vantage points: damage theories and programmed theories.
Damage theories view agingas the result of
accumulated
errors, from free radicals for example. Programmed theories view aging as the result of genetic
regulation. These paradigms are not contradictory, but complementary. Changes in gene
expression that occur with cellular aging permit damage that does not occur (or accumulate) in
immortal cell lines such as germ cells. The issue is not whether free radical damage underlies
much of aging-- it clearly does-- but the more complex question of whether we may learn to
control the onset and timing of such damage, which ultimately determines our health and our
maximum life span.

CLONES, CANCER, AND AGING CELLS

The mean human life span has been extended
remarkably
over the past two centuries; the maximum life span has not [6].This has resulted in a "rectangularization" of life span, in which mortality is
increasingly
becoming compressed against an apparently fixed end point: the maximum human life span of
approximately 120 years [7]. Over the past decade, however, several laboratories have
successfully extended the maximum life spans of at least two multicellular species genetically
(Drosophila [3]and Caenorhabditis
elegans [8-10])and several more by dietary restriction [11-13]. That this increase in
maximum life span can occur at all invalidates the dogma that maximum life span is fixed, and it
thus invalidates the inevitability of the rectangularization model described above. That it occurs
with such minimal genetic manipulation and that the effect is so substantial (two gene mutations
increase the maximum life span of C. elegans six-fold) raise the provocative question of
what might lie in store for clinical medicine. To a first approximation, the increased life span
occurs predominantly through the genetic control of free-radical metabolism. This is not
unexpected: cellular aging (and modifications of maximum life span) operates predominantly
through the damaging effects of free radicals [14,15]. Not only does free radical production
increase substantially as cells age, but the free radicals produced are less well contained and less
efficiently mopped up by free radical scavengers, and their consequent damage is less efficiently
repaired. This simplification leaves unanswered the questions of how cancer cells and the germ
cell lines avoid aging damage, though they have comparable genomes, mitochondria, and free
radicals. Telomere shortening (and its consequent effects on gene expression and cell cycle
mechanisms) is implicated in allowing cancer and other cell lines to avoid cell senescence
[16,17].
Free radical damage appears to be the major cause of the damage that occurs in aging cells
[18,19], but the more complex issue lies in the control of the timing and release of such damage
[20].

What is the age of a cell? Unless we measure age from every new
division (as we do in Saccharomyces, for example, in which
the asexual form shows aging in that "maternal" cells have a limited number of divisions, but the
number is "reset" in each new "daughter" cell), newly divided cells each inherit the same age as
the single cell from which they derived. All cells-- as unbroken cell lines-- have, reductio ad
absurdum, the same age. Life on this planet is 3.5 billion years old, and all life and every cell
are equally old in a peculiar sense. But then how is the onset of free radical damage timed, if not
simply by years of a cell's life? Aging does not occur for 3.5 billion years in the germ cell line,
yet
it clearly does so beginning sometime after fertilization. Free radical aging is not timed by the
profoundly archaic age of the entire cell lineage, but rather by a clock that begins running only
after fertilization (in multicellular organisms; in the asexual phase of unicellular organisms such
as
yeasts, aging is considered to commence at the asymmetric division of a daughter cell as she
buds
off the larger mother cell). Humans and other multicellular organisms derive from cells that do
not
show the loss of replicative ability and the morphologic and gene expression changes that are
characteristic of senescent cells [1,21,22] until after the
organism achieves multicellularity. Age per se does not determine aging; it is altered
genetic expression that somehow permits the onset of aging to occur.

The onset and progression of aging is strongly affected by
chromosomal
structure[23] and gene expression[24]. Evidence from work on early aging syndromes (progerias)
supports this observation. Patients with Werner's syndrome have an average life span of 47 years
and a known defect in helicase metabolism that results in abnormal chromosomal "unwinding"
and
replication [25]. Patients with Hutchinson-Gilford syndrome have an average life span of 12.7
years, and their skin fibroblasts have telomere lengths characteristic of cells from far older
patients
[26-27].

The cloning of mature ovine mammary cells likewise raises
the question of whether age can be reset. Wilmut, et al,
[28] have shown that gene expression can be reset: in this case at least the six-year-old adult
mammary cells from the donor have not yet been irreversibly aged by time per se or by
the
aging of the donor organism. To the contrary, successful cloning demonstrates that these cells
still
have sufficient intact genetic information available to allow reconstitution of an apparently
healthy
multicellular organism. But was Dolly-the cloned organism-- six years old at birth, or had her
cells
been reset to age zero? The most tempting and certainly viable hypothesis is that genes can be
reset to reflect the cellular age consistent with a developing organism [29], a hypothesis that is
now (in Dolly's ease) finally being tested. A considerable body of evidence suggests that cell
aging
does not occur because of accumulated DNA damage or poor transcription fidelity [30]; rather,
the DNA is intact and transcription is intact, but transcription occurs at lower rates and in
significantly altered patterns as cells age [21,23]. If Dolly's cells show normal ovine aging for
her"new" age rather than being six years old at birth, then this will provide further
support for the hypothesis that age can be reset even after it has been in progress. The nature of
this putative resetting mechanism will be a prime target for further research.

Cancer research has also prompted revision of our views of cell aging
[22]. The problem in oncology is not that cells age and die, but that they do not. Normal somatic cells have well-defined limits to
replication. Young skin fibroblasts typically have 50 divisions before they show cellular
senescence. Within the past seven years, there has been increasing support for the model that
cellular senescence in normal (noncancerous) human cells is the result of an altered (and, for the
cell, dysfunctional) pattern of gene expression, and that the onset and progression of this pattern
of senescent gene expression is regulated (through insufficiently understood mechanisms likely
to
involve heterochromatin changes) regulated by the telomeres [31-33]. Most cancer cells,
however, are biologically immortal and will continue dividing indefinitely under appropriate
conditions. This potential is linked to their expression of telomerase [34-37]. Additionally, it
appears that most, perhaps all, cancer cells are fundamentally different with regard to their
aberrant cell-cycle braking systems. Typically, 60% of combined human cancers (70% of colon
cancers, 40% of breast cancers) have an aberrant p53. If we include p2l, D cyclins,
cyclin-dependent kinases, and other parts of the cell cycle "machinery," the percentage of cell
cycle abnormalities might approach 100% of cancers [38,39]. More recently, evidence is
accumulating that at least 90% of cancer cells from human malignancies are also capable of
resetting their telomere lengths and evading cell senescence [40]. This model has proven a
powerful predictor not only of cell aging, but also of cancer cell survival [41].

This realization-- that the aging process is mutable at the cellular level
and the implications of this for age-related diseases-- has itself spawned more than a dozen
targeted biotechnology companies over the past four years [42]. Not only does this realization
have implications for cellular aging, but it has also prompted rethinking of the historically
warranted pessimism about curing cancer. As a Scienceeditorial put it at the end of 1996, predicting whether we might cure cancer, "the
standard answer-- 'No'--- may be up for revision [43]. Such optimism is not novel, but a
comprehensive conceptual base, good supporting data, and promising clinical trials are new and
very welcome.

The recent cloning of the protein component of human telomerase [36]
will only accelerate this already rapid progress in understanding cancer and cell senescence.
More
importantly, to the extent that we can affect cell senescence therapeutically, we may stand to alter
age-related diseases and thereby their economic, social, and human outcomes.

AN EVOLVING
MODEL

Previously, aging was seen as an immutable, passive
accumulation of entropic damage in the cell. The evolving paradigm, in which cell aging results
from and is coordinate on altered gene expression [29,32,33] is growing in acceptance. Although
still nascent, the Senescent Gene Expression (SGE) model is a model that encompasses both the
programmed and damage schools-of-thought on aging. It suggests that aging is a complex
cascade of processes that include repeated cell division, telomere effects at the chromosome ends
(due to both their lengths and their associated heterochromatin), a significantly altered pattern of
senescent gene expression in "old" cells, and consequent alterations in cell metabolism in general
and free-radical metabolism (production, sequestration, trapping, and damage repair) in
particular.
In addition, even cells that do not directly demonstrate aging changes (e.g., myocardial cells) depend
on those that do (e.g., vascular endothelial cells). Together this cascade
of processes play a coordinated but complex role in aging and-- far more importantly-- identification of each step could provide a
basis for developing therapeutic interventions to affect either a single step or the whole. This
model-- that the process of aging in the cell can be altered or reset (as may be true in the cloning
of adult sheep cells and as is demonstrably true in senescent fibroblast hybridomas [44]-- undermines the
historical certainty that aging and age-related diseases are immutable at the cellular level. Coordinate and
similar
shifts are occurring in our understanding of cancer. Differences at the heart of cancer cells, such
as cell cycle errors and telomerase
expression, may provide leverage to draw far clearer therapeutic lines than we now can between
cancers and normal cells. While none of our currently altering views of cancer or aging promise a
cure, enormous clinical potentials may be opening for us where none existed previously [43,45,46].

These changes in our theoretical understanding of cell aging and the
availability of data to support the mutability of cell aging together call into question our ability to
provide accurate extrapolations of the social and economic consequences of projected aging in
developed countries. In 1950, four years before the Salk vaccine, if we were to have predicted the
medical costs (e.g., iron lungs) that would
accrue from polio over the next decade, we would have risked similar inaccuracies. Predictions
of
the costs of aging will be hollow unless they factor in the ongoing, nascent, and fundamental changes in our
understanding
of aging and age-related diseases.

POLICY IMPLICATIONS OF EXTENDING
LIFE

We are currently incapable of altering the aging process
in any meaningful way, and any assertion to the contrary is misleading and not supported by fact.
It is, however, equally misleading and disingenuous as well to ignore the ongoing shift in our
knowledge of cell biology as we attempt to predict the future of health care and social policy in
the United States and other developed countries. The assumptions on which we base our
predictions need to be clearly understood, and there exists a reasonable degree of uncertainty in
assuming that aging and age related diseases will remain immutable in the coming
decades.

The fiscal and social implications of this possibility cannot be underestimated. Any increase in the life
span will be accompanied by concomitant shifts in social spending on the aged, but we cannot
reasonably estimate the timing, magnitude, or fiscal outcome of altering the maximum human
life
span and age-related diseases. Even if one denies the possibility of such alteration, the upward
trend in median age of the world's population is substantial but of uncertain magnitude. Even
assuming that the lifespan is fixed,
the consequent rectangularization of the survival curve,
described by Fries [7], will exert fiscal and social pressures on our ability to care for the elderly [47,48]. The magnitude of
these pressures, their global distribution, and their effect on well-being will depend on several
factors.

First, while there exists some variation internationally in the health
status of elderly cohorts [49,50],
the social costs of increasing the maximum human life span will largely depend on the level of
functional impairments and chronic disabilities among the aged [51,52]. Recent research suggests that, at least in the United
States, increases in the mean life span have been accompanied by a concomitant decline in the prevalence of
morbidity and disability among the aged [53,54]. The magnitude of any such decline and its
overall impact on health care costs, relative to prior elderly cohorts, will vary internationally as a
function of a nation's health care system, preventive health measures, rate of technological
diffusion, advances in the treatment of acute and chronic diseases, social and political structures,
and economic systems-- to mention a few. The possibility that we might delay or prevent aging
and associated disabilities only increases the already considerable variance in estimating such
costs. However, the impact of such innovations would be determined by the political, social,
regulatory, and economic structures of each country.

Second, innovations in medical technology (therapeutic, diagnostic, or
organizational) for age-related conditions need not coincide with the health care needs or
necessarily promote the well-being of those in developing countries. The immediate and future
medical and public health concerns of sub-Saharan Africa are not in the research, development,
and diffusion of age-related technologies, but in the development of effective mechanisms for
controlling the spread of
infectious diseases (such as the Acquired Immunodeficiency Syndrome [55], malaria,
and
tuberculosis), and the fatal consequences of drought, famine, and civil wars, which lead to mean
life spans in these countries of approximately 48 years [56]. Therefore, when considering the
international fiscal effects of increasing the maximum healthy human life span and the impact of
these innovations on functional impairment among the aged, it is important to acknowledge that
these advances are likely to benefit developed nations preferentially.

Third, the continued decline in the level of functional impairment
among
the elderly populations in developed countries, along with increases in active life expectancy [57,58], has profound
implications for work and retirement years. Even though the effect of longevity on work and
retirement choice remains unclear [59], developed nations can expect years of productive life
among elderly age-specific cohorts to increase. How altering the maximum human life span-- by
whatever magnitude-- would alter this effect cannot be reliably projected, but contrary to what
one might expect, increased life expectancy in the United States has been associated with an
accelerated decline in the labor force participation rates of older persons for the past 50 years
[60]. To sustain current levels of well-being, however, longer life spans will have to be
accompanied by either correspondingly longer work years, or higher premiums to enhance
private
contributions to retirement accounts, or higher taxes to enhance contributions into social
insurance accounts. The magnitude of the latter will be determined by the willingness of current
generations to subsidize future generations, as well as the ratio of workers to retirees. Further, the
structure of public and private pension funds can in themselves affect the labor force
participation
rates of individuals. The retirement income provided by the funds allows older workers to leave
the labor force at younger ages and still support themselves in retirement years [60]. Hence, it is
the interplay among mortality, health status, work, and retirement and the structure of retirement
accounts that will determine the overall impact of the burgeoning aging population and any
increase in the maximum human life span on the fiscal health of nations.

Finally, with increasing relative numbers of the aged, along with the
growth in the proportion of the oldest old by the year 2040 [61], the international demand for long-term care could
impose unexpected pressures on governments and individuals. This will be exacerbated if the
proportion of offspring willing to live with their elderly parents continues to decline internationally [62], therefore placing
greater pressures on the public and private sectors for the establishment of innovative alternatives
to long-term care-such as home or community-based care. The magnitude and direction of these
pressures depend critically on the extent to which the maximum life span may
be
altered and the degree to which the prevalence of disabilities will be modified. Neither of these
effects can be reliably estimated, yet current research suggests there is a reasonable possibility
that
both might alter within the time frame of current attempts to project future trends in international
health and social welfare expenditures.

CONCLUSION

We should exercise extreme caution
in
projecting the future social and economic impact of an aging global society. This is particularly
so
because our understanding of the biology of aging is changing. The unquestioned conviction that
we cannot alter aging and the cellular underpinnings of the diseases that accompany the aging
process is no longer strictly tenable. The possibility that aging and its consequent clinical
outcomes may be alterable at the cellular and chromosomal levels remains merely speculative
and
needs to be considered cautiously. However, such speculation becomes increasingly appropriate
if
we are to make any attempt to predict the future costs of an aging global society. It is important
that we
qualify and carefully define our assumptions to include the possibility that the morbidity and the
mortality rates of age-related diseases, along with the maximum human life span itself, may be
altered in the near future.

This research was partially supported by
the
National Institute on Aging-- funded Center on the Economics and Demography of Aging (P20-AG12839). The authors
gratefully acknowledge the advice of Donald Ingram, David Smith, Robert Arking, David Kirp, Ron Lee, and Jane Mauldon.